Magnetic microparticles have many applications in such diverse fields as clinical biology, chemistry, medicine, electronics and physics. For example, in the field of clinical biology, small magnetically responsive particles have been used in vitro separations, where the particle is coated and/or functionalized so that a reactive group, such as an affinity agent, can be attached to the particle. The particles are then dispersed in a sample, where reactive groups or affinity agents react specifically with a target molecule. The magnetic particle containing the target molecule is then recovered by applying a magnetic field to the sample, thereby separating the magnetic particles from the sample. The target molecules can then be removed from the magnetic particles. Magnetic particles functionalized with chemically reactive groups can be used in chemical separations. Separation techniques using magnetic particles are well known in the art. Molday et al., Nature, 268:437-438 (1977); B.L. Hirschbein et al., Chemtech, March, 1982, pp. 172-179 (1982); M. Pourfarzaneh. The Ligand Quarterly, 5(1):41-47 (1982); Josephson, U.S. Pat. No. 4,672,040 (1987) and references cited therein.
Very small magnetic particles have important medical applications in the fields of in vivo imaging. In one application, the magnetically responsive particles are utilized as contrast agents for magnetic resonance imaging (MRI). MRI is used for a variety of clinical diagnostic purposes, including detection of cancerous lesions in reticuloendothelial tissues, detection of intenstinal lesions, or liver diseases, such as hepatitis and cirrhosis. Clinical usage of MRI for diagnostic purposes is described, for example, by Groman and Josephson in U.S. 4,770,183 (1988); Pykett et al., Nuclear Magnetic Resonance, pp. 157.167 (April, 1982) and T F. Budinger et al., Science, pp. 288.298 (October, 1984). Contrast agents are used in MRI to define selected tissues and to differentiate from surrounding tissue.
Magnetically responsive particles also have many applications in the fields of electronics and computers. For example, ferrofluids containing small magnetically responsive particles dispersed in a carrier fluid are used as seals in computer disk drives, when they act as spindle sealants and as electrical grounds to prevent an electrical charge from building up in the drive shaft. Small magnetic particles dispersed in various polymeric carriers have been used to coat magnetic tapes and to form magnetic stripes which can be used to store information The use of ferrofluids in magnetic recording media and as sealants in computer disk drives has been described in: Ootani et al. U.S. Pat. No. 4,786,551 (1988); Papalos U.S. Pat. No. 4,770,952 (1988); Yamaguchi et al., U.S. Pat. No. 4,420,532 (1983); Bradshaw et al. U.S. Pat. No. 4,454,282 (1984); Koike et al., U.S. Pat. No. 4,407,721 (1983); Borduz and Raj, U.S. Pat. No. 4,604,229 (1986) and U.S. Pat. No. 4,604,222 (1986); Rosenswerg, U.S Pat. No. 3,620,584 (1971); and Chagnon, U.S. Pat. No. 4,356,092 (1982).
Small magnetic particles can exhibit different types of magnetic behavior based on their crystal size. The particles may be ferromagnetic, paramagnetic or superparamagnetic. Ferromagnetism occurs in particles in which the unpaired electrons in the magnetic materials interact, that is, they are highly coupled. Ferromagnetic materials are characterized by high magnetic susceptibilities in the presence of an applied magnetic field, and they retain their magnetic properties after the externally applied magnetic field has been removed. Magnetic susceptibility is the degree of response to an applied magnetic field. Ferromagnetism results only when the unpaired electrons are contained in a crystalline lattice or metallic complex and is not a property of individual molecule-like ions in solutions or gases. Ferromagnetic materials include metallic iron and certain metal oxides such as gamma ferric oxide (gamma-Fe.sub.2 0.sub.3) or magnetic particles which are larger then about 0.1 micron in diameter.
Paramagnetism occurs in particles that contain unpaired electrons which do not interact, and are not coupled, such as ions in solutions or gases with unpaired electrons. Paramagnetic materials are characterized by a weak magnetic susceptibility. Paramagnetic particles become weakly magnetic in the presence of a magnetic field, and rapidly demagnetize once the external field is removed.
Superparamagnetic particles possess characteristics of both paramagnetic and ferromagnetic materials. Like paramagnetic particles, superparamagnetic particles rapidly demagnetize after the external magnetic field is removed; and like ferromagnetic particles, possess high magnetic susceptibility. Iron oxides such as magnetite or gamma ferric oxide exhibit superparamagnetic behavior when the crystal diameter falls significantly below that of ferromagnetic materials For cubic magnetite and gamma ferric oxide, this crystal diameter is about 300 angstroms (.03 microns) J. Dunlop, J. Geophys. Rev., 78:1780 (1972; Bate In: Ferromagnetic Materials, Vol. 2 Wohlfarth (ed.), p. 439 (1980). Since iron oxide crystals are generally not of a single uniform size, the average size of purely ferromagnetic iron oxides is substantially larger that 300 angstroms. For example, ferromagnetic iron oxide used in magnetic recording materials consists of needle-like particles which are about 0.35 microns long and 0.06 microns thick. Ferromagnetic particles for data recording are generally between 0.1 and 10 microns in length. Jorgenson, The Complete Handbook of Magnetic Recording, p.35 (1980). For a given type of metal or metal oxide crystal, purely ferromagnetic crystals have average dimensions many times larger that purely superparamagnetic crystals of the same material.
Magnetic particles exhibiting specific forms of magnetic behavior are appropriate for applications in the various diverse fields in which such particles are used. For example, for use in MRI, superparamagnetic particles are preferred because superparamagnetism profoundly alters nuclear magnetic reasonance (NMR) images. Ferromagnetic particles are preferred for use in most electronic, magnetic recording and computer applications. Thus, a method for making magnetic particles having desired properties would be useful for many applications.